Undecan-4-olide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no data

Reliability:

4 (not assignable)

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1962

Report date:

1962

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Determination of the degree of breakdown under in vitro digestion conditions using intestinal fluid

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Undecan-4-olide

EC Number:

203-225-4

EC Name:

Undecan-4-olide

Cas Number:

104-67-6

Molecular formula:

C11H20O2

IUPAC Name:

5-heptyloxolan-2-one

Details on test material:

- Name of test material (as cited in study report): Gamma-Undecalactone CP; so called Aldehyde C-14
- Laboratory reference sample: B-7095
- Source: Givaudan
- Physical state: no data
- Analytical purity: 97.0 % (as determined by alkali consumption)
- Stability under test conditions: no data
- Storage condition of test material: no data

Radiolabelling:

no

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Administration / exposure

Details on exposure:

Not applicable

Duration and frequency of treatment / exposure:

15, 30, 45, 60, 240 minutes

Doses / concentrations

Dose / conc.:

1 other: mM

No. of animals per sex per dose / concentration:

Not applicable

Positive control reference chemical:

None

Details on study design:

1 mM of gamma-undecalactone was incubated and shaken at 37 °C, with 50 mL portions of simulated intestinal fluid for 15, 30, 45, 60 and 240 minutes. The simulated fluid is that described in the United States Pharmacopeia and consists of an aqueous mixture of monoblastic potassium phosphate, sodium hydroxide, and pancreatin adjusted to pH 7.5.

Details on dosing and sampling:

Following incubation, the solutions were extracted with ether and the unconverted gamma-undecalactone determined by adding standard alkali, heating, and back titrating the unconsumed base with standard acid. Results were calculated with respect to the known quantity of gamma-undecalactone present in the analytical sample, as determined by duplicate purity measurements. These were carried out by addition of one gram of each lactone to 25 mL of 0.5 N alcoholic potassium hydroxide. The solution was refluxed for one hour on a steam bath and then back-titrated with 0.1 N hydrochloric acid.

Statistics:

None

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Not applicable

Any other information on results incl. tables

Partial conversion by the intestinal fluid was observed (See Table 7.1.1/1). Increased time (240 minutes) and/or doubling volume of intestinal fluid does bring about further ring opening although still not complete. It appears that pH is a rather critical factor in these experiments, and that the 7.5 value at the onset of the exposure constitutes the borderline of a "go-no-go" reaction for gamma-undecalactone. The small decrease brought about during the first minutes of exposure, as a result of alkali consumption for ring opening, sufficiently lowers the pH to virtually a non-reactive condition. Increased quantities of base available from the doubled volume exposures, permits a greater degree of reaction in a shorter period of time. Increased time (to four hours) with a single volume of intestinal fluid allows the gamma-undecalactone to proceed further.

Table 7.1.1/1: Lactone opening in intestinal fluid

Sample	Purity (%)	Degree of lactone opening with time (%)
		15 min	30 min	45 min	60 min	60* min	240 min	240* min
Gamma-undecalactone	97.0	24	19	22	19	68	58	62

* using twice the quantity (100 mL) of intestinal fluid per millimole.

A 1-h incubation of 1 mmol 4,4-dibutyl-Ɣ-butyrolactone and omega-6-hexadecenlactone with 50 mL of simulated intestinal fluid resulted in 92% and 96% hydrolysis, respectively, yielding the ring-opened hydroxycarboxylic acids. Ninety-two percent of the omega-6-hexadecenlactone was hydrolysed within the first 15 min of incubation. Incubation of 1 mmol ofƔ-valerolactone and Ɣ-undecalactone with 50 mL of simulated intestinal fluid resulted in 32% and 58% hydrolysis within 4 h, respectively. Doubling the volume of intestinal fluid resulted in a 50% and 62% hydrolysis of Ɣ-valerolactone andƔ-undecalactone, respectively, within the same period of time

Applicant's summary and conclusion

Conclusions:

Only partial conversion of γ-Undecalactone by the intestinal fluid was observed.

Executive summary:

The degree of breakdown of γ-Undecalactone and γ-Nonalactone under in vitro digestion was determined using intestinal fluid.

Incubation of γ-Nonalactone and γ-Undecalactone with rat liver homogenate in buffer solution at pH 7.5 resulted in 62–94% and 26–40% hydrolysis within 1 h, respectively. After 1 h, 81–88% and 45–70% hydrolysis of γ-Nonalactone andγ-Undecalactone, respectively, occurred at pH 8.0.

Only partial conversion of γ-Undecalactone by the intestinal fluid was observed. Increased time (240 minutes) and/or doubling volume of intestinal fluid does bring about further ring opening although still not complete. It appears that pH is a rather critical factor in these experiments, and that the 7.5 value at the onset of the exposure constitutes the borderline of a "go-no-go" reaction for γ-Undecalactone.

The small decrease brought about during the first minutes of exposure, as a result of alkali consumption for ring opening, sufficiently lowers the pH to virtually a non-reactive condition. Increased quantities of base available from the doubled volume exposures, permits a greater degree of reaction in a shorter period of time. Increased time (to four hours) with a single volume of intestinal fluid allows the γ-Undecalactone to proceed further.